Clinical Research in Cardiology (2020) 109:616–627

https://doi.org/10.1007/s00392-019-01549-0

ORIGINAL PAPER

Association between anemia and hematological indices with mortality

among cardiac intensive care unit patients
Hamza A. Rayes1 · Saraschandra Vallabhajosyula1,2 · Gregory W. Barsness2 · Nandan S. Anavekar2 · Ronald S. Go3 ·
Mrinal S. Patnaik3 · Kianoush B. Kashani1,4 · Jacob C. Jentzer1,2 

Received: 2 July 2019 / Accepted: 11 September 2019 / Published online: 18 September 2019
© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Background  Anemia and elevated red cell distribution width (RDW) or mean corpuscular volume (MCV) are associated
with an adverse prognosis in patients with cardiovascular disease and critical illness. Limited data exist regarding these
associations in unselected cardiac intensive care unit (CICU) patients.
Methods  Retrospective cohort study of CICU patients between January 1, 2007, and December 31, 2015, with a hemoglobin
(Hb) level measured at admission. Multivariable regression was performed to determine predictors of hospital mortality, and
Kaplan–Meier analysis was used to determine post-discharge survival.
Results  We included 9644 patients with a mean age of 67.5 ± 15.1 years, including 3604 (37.4%) females. The median (IQR)
values of Hb, MCV and RDW were 12.2 g/dL (10.6, 13.7), 90.7 fL (87.3, 94.2) fL, and 14.1% (13.3, 15.8), respectively.
Anemia (admission Hb < 12 g/dL) was present in 4434 (46%) patients. A total of 845 (8.8%) patients died in the hospital.
Patients with anemia had higher hospital mortality (11.3% vs. 6.6%, unadjusted OR 1.82, 95% CI 1.58–2.10, p < 0.001). After
multivariable regression, admission Hb and MCV were not significantly associated with hospital mortality (both p > 0.1),
while admission RDW (adjusted OR 1.12 per 1%, 95% CI 1.07–1.18, p < 0.001) was significantly associated with hospital
mortality. Hospital survivors with lower Hb, higher MCV, or higher RDW had lower post-discharge survival.
Conclusion  Elevated RDW on admission was independently associated with higher hospital mortality in CICU patients.
These data emphasize the importance of hematologic abnormalities for mortality risk stratification in CICU populations.

Hamza A. Rayes and Jacob C. Jentzer contributed equally to this

work.

Electronic supplementary material  The online version of this

article (https​://doi.org/10.1007/s0039​2-019-01549​-0) contains
supplementary material, which is available to authorized users.

* Jacob C. Jentzer Kianoush B. Kashani

jentzer.jacob@mayo.edu kashani.kianoush@mayo.edu
Hamza A. Rayes 1
Division of Pulmonary and Critical Care Medicine,
hamzarayes@outlook.com
Department of Medicine, Mayo Clinic, 200 First Street SW,
Saraschandra Vallabhajosyula Rochester, MN 55905, USA
vallabhajosyula.saraschandra@mayo.edu 2
Department of Cardiovascular Medicine, Mayo Clinic, 200
Gregory W. Barsness First Street SW, Rochester, MN 55905, USA
barsness.gregory@mayo.edu 3
Division of Hematology and Oncology, Department
Nandan S. Anavekar of Medicine, Mayo Clinic, Rochester, MN, USA
anavekar.nandan@mayo.edu 4
Division of Nephrology and Hypertension, Department
Ronald S. Go of Medicine, Mayo Clinic, Rochester, MN, USA
go.ronald@mayo.edu
Mrinal S. Patnaik
patnaik.mrinal@mayo.edu

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Clinical Research in Cardiology (2020) 109:616–627 617
Graphic abstract
Keywords  Red cell distribution width · Anemia · Mean corpuscular volume · Cardiac intensive care unit · Coronary care
unit · Mortality
Introduction
Anemia is common among acutely ill cardiac patients, with
a prevalence of up to 19% and up to 48% among patients
with acute coronary syndrome (ACS) and acute heart failure
(HF), respectively [1, 2]. Anemia is an independent predic-
tor of adverse cardiovascular events, bleeding, and mortal-
ity in patients with acute cardiac disease [1–5]. In addition,
abnormal values of hematological indices, including red cell
distribution width (RDW) and mean corpuscular volume
(MCV) have also been associated with worse outcome in
patients with acute cardiac disease [6–12]. In general inten-
sive care unit (ICU) populations, the presence of anemia
has been associated with demand myocardial ischemia, ICU
readmission, and increased mortality [13–15]. As in patients
with cardiac disease, elevated RDW and MCV are also asso-
ciated with worse outcomes in general ICU patients [16–18].
Despite the growing similarities between the cardiac inten-
sive care unit (CICU) and medical ICU populations, CICU
patients remain distinct due to their more prevalent cardiac
comorbidities [19]. It remains uncertain whether predictors
of mortality in general ICU patients without acute cardiac dis-
ease or in non-ICU patients with acute cardiac disease would
apply similarly to the specialized CICU population. There is a
paucity of published data available to describe the association
between anemia, RDW, and MCV and adverse outcomes in
CICU patients. This study was designed to test the hypothesis
that anemia and abnormal values of RDW and MCV are asso-
ciated with higher mortality in CICU patients.
Methods
Study population
This study was approved by the Institutional Review Board of
Mayo Clinic as posing minimal risk to patients and was con-
ducted under a waiver of informed consent (IRB # 16-000722).
We retrospectively analyzed a database of consecutive unique
adult (aged ≥ 18 years) patients admitted to the CICU at Mayo
Clinic Hospital St. Mary’s Campus whose entire CICU admis-
sion occurred between January 1, 2007, and December 31,
2015, as previously reported [20–22]. We only analyzed data
from the first CICU admission during the study period to avoid
mortality bias associated with CICU readmissions. According
to Minnesota state law statute 144.295, patients must provide
authorization to be included in observational research stud-
ies; patients who did not have Minnesota Research Authori-
zation were excluded from the database. Patients who did not
have available data for admission hemoglobin (Hb) level were
excluded from this study.
Data sources
Demographic, vital sign, laboratory, and other clinical and
outcome data were extracted electronically from the medical
13

618
record, including procedures and therapies performed dur-
ing the CICU and hospital stay. The admission value of all
vital signs, clinical measurements, and laboratory values
was used, defined as either the first value recorded after
CICU admission or the value recorded closest to CICU
admission. Although the WHO defines anemia as an admis-
sion Hb level < 12 g/dL in women and < 13 g/dL in men,
we chose an operational definition of anemia as admission
Hb < 12 g/dL regardless of gender [23]. Microcytosis was
defined as an MCV < 80 fL and macrocytosis was defined as
an MCV > 100 fL [23]. The Acute Physiology and Chronic
Health Evaluation (APACHE)-III score, APACHE-IV pre-
dicted hospital mortality and Day 1 Sequential Organ Failure
Assessment (SOFA) score were calculated for all patients
using data from the first 24 h of CICU admission, with miss-
ing variables imputed as normal as the default; the mean and
maximum values of all daily SOFA scores while the patient
remained in the CICU were recorded [20–22, 24, 25]. The
Charlson Comorbidity Index (CCI) and individual comor-
bidities were determined based on a previously-validated
electronic algorithm [26]. Discharge diagnoses were identi-
fied using International Classification of Diseases (ICD)-9
and ICD-10 diagnosis codes, these diagnoses were not mutu-
ally exclusive, and the primary discharge diagnosis could
not be determined.
Statistical analysis
The primary outcome was all-cause hospital mortality,
and the secondary outcomes were CICU mortality and
5-year post-discharge mortality, based on the electronic
review of the medical record. Groups were compared using
Student t test and ANOVA for continuous variables and
Pearson Chi-square test for categorical variables. Logistic
regression was used to calculate the unadjusted odds ratio
(OR) and 95% confidence interval (CI) values for hospital
mortality. Optimal cutoffs for predicting hospital mortal-
ity were determined from receiver-operator characteristic
curves based on the highest value of Youden’s J index
(sensitivity + specificity −1). Multivariable analysis was
performed to determine adjusted OR values for hospital
mortality using an adaptive elastic net penalized logis-
tic regression model, with candidate variables including
demographics, comorbidities, illness severity, and CICU
therapies and complications; an interaction term between
Hb and RDW was included in the model [27]. Optimal tun-
ing parameters for the elastic net were selected by linear
grid search in conjunction with tenfold cross-validation to
maximize the AUROC. Kaplan–Meier survival analysis
was used to compare 5-year post-discharge survival among
patients surviving to hospital discharge (hospital survi-
vors), with groups compared using the log-rank test. Cox
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Clinical Research in Cardiology (2020) 109:616–627
proportional-hazards analysis was used to determine the
associations between Hb, MCV, and RDW with post-dis-
charge mortality after adjusting for predictors of hospital
mortality. Two-tailed p values < 0.05 were considered sta-
tistically significant. Statistical analyses were performed
using JMP version 13.0 Pro (SAS Institute, Cary, NC).
Results
Study population and baseline characteristics
We screened 12,904 CICU admissions and excluded 2900
as previously described, leaving 10,004 patients in the
database [20–22]. An additional 360 patients were further
excluded due to lack of available data on admission Hb
level, leaving 9644 patients in the final study population
(Supplemental Fig. 1). The median age of the study popu-
lation was 69.1 years (IQR 57.8, 78.9) and comprised 3604
(37.4%) females. The median CCI was 2 (IQR 0, 4), with
a median APACHE-III score of 58 (IQR 45, 74) corre-
sponding to a median APACHE-IV predicted mortality of
9.5% (IQR 4.0, 22.8). The median admission Hb level was
12.2 g/dL (IQR 10.6, 13.7); 4434 (46.0%) patients met our
operational definition of anemia (admission Hb < 12 g/dL),
while 5402 (56.0%) met the WHO gender-specific defini-
tion of anemia (46.3% of women and 53.7% of men). Data
on MCV were available in 9409 (97.5%) patients (Sup-
plemental Fig. 1), and the median MCV was 90.7 fL (IQR
87.3, 94.2). Data on RDW were available in 9405 (97.5%)
patients (Supplemental Fig. 1), and the median RDW was
14.1% (IQR 13.3, 15.6). Patients with anemia were older,
more frequently female, had higher rates of comorbidities,
greater illness severity and increased utilization of CICU
therapies (all p < 0.05) compared to patients without ane-
mia (Table 1); in addition, patients with anemia were more
likely to have a discharge diagnosis of HF and less likely
to have a discharge diagnosis of ACS. Significant differ-
ences were observed in baseline characteristics, comor-
bidities, illness severity and CICU therapies across RDW
quartiles, reflecting higher illness severity, more extensive
comorbidities, lower Hb and greater use of CICU therapies
in patients with higher RDW (Supplemental Table 1); the
prevalence of HF increased and the prevalence of ischemic
heart disease decreased with rising RDW quartile. Patients
with a discharge diagnosis of HF had lower Hb (11.7 vs.
12.4  g/dL) and higher RDW (15.7% vs. 14.2%), while
patients with a discharge diagnosis of ACS had higher Hb
(12.5 vs. 11.9 g/dL) and lower RDW (14.1% vs. 15.3%)
(all p < 0.001); MCV differed minimally between these
groups.
Clinical Research in Cardiology (2020) 109:616–627 619

Table 1  Baseline characteristics Overall popula- Patients without Patients with ane- p value
of the study population, patients tion (n = 9644) anemia (n = 5210) mia (n = 4434)
with and without anemia
(admission hemoglobin < 12 g/ Demographics
dL)
 Age 67.5 ± 15.1 64.8 ± 15.0 70.6 ± 14.7  < 0.001
 Female gender 3604 (37.4%) 1448 (27.8%) 2156 (48.6%)  < 0.001
 White race 8911 (92.4%) 4860 (93.3%) 4051 (91.4%)  < 0.001
 BMI (kg/m2) 29.6 ± 7.0 29.8 ± 6.8 29.3 ± 7.3  < 0.001
 CICU length of stay 2.6 ± 4.6 2.4 ± 4.1 2.8 ± 5.2  < 0.001
 Hospital length of stay 8.1 ± 13.3 6.4 ± 9.0 10.0 ± 16.9  < 0.001
 CICU mortality 519 (5.4%) 229 (4.4%) 290 (6.5%)  < 0.001
 Hospital mortality 845 (8.8%) 342 (6.6%) 503 (11.3%)  < 0.001
Severity of illness
 APACHE-III score 61.7 ± 25.2 56.3 ± 24.8 68.0 ± 24.2  < 0.001
 APACHE-IV predicted mortality 0.172 ± 0.202 0.142 ± 0.193 0.207 ± 0.206  < 0.001
 Day 1 SOFA score 3.6 ± 3.2 3.1 ± 3.1 4.3 ± 3.3  < 0.001
 Maximum week 1 SOFA score 4.1 ± 3.4 3.5 ± 3.2 4.8 ± 3.5  < 0.001
 Mean week 1 SOFA score 3.1 ± 2.7 2.6 ± 2.5 3.6 ± 2.8  < 0.001
Comorbidities
 Charlson comorbidity index 2.4 ± 2.6 1.7 ± 2.2 3.2 ± 2.9  < 0.001
 Prior myocardial infarction 1919 (19.9%) 923 (17.8%) 996 (22.5%)  < 0.001
 Prior heart failure 1901 (19.5%) 709 (13.6%) 1192 (26.9%)  < 0.001
 Prior stroke 1179 (12.3%) 508 (9.8%) 671 (15.2%)  < 0.001
 Prior chronic kidney disease 1971 (20.5%) 603 (11.6%) 1368 (30.9%)  < 0.001
 Prior diabetes mellitus 2752 (28.6%) 1163 (22.4%) 1589 (35.9%)  < 0.001
 Prior cancer 2053 (21.3%) 868 (16.7%) 1185 (26.8%)  < 0.001
 Prior lung disease 1880 (19.5%) 835 (16.1%) 1045 (23.6%)  < 0.001
 Prior liver disease 190 (2.0%) 64 (1.2%) 126 (2.8%)  < 0.001
 Prior dialysis 562 (5.8%) 144 (2.8%) 418 (9.4%)  < 0.001
Discharge ICD-9 diagnoses
 Shock 1032 (10.7%) 454 (8.7%) 578 (13.0%)  < 0.001
 Cardiogenic shock 809 (8.4%) 390 (7.5%) 419 (9.5%)  < 0.001
 Cardiac arrest 769 (8.0%) 427 (8.2%) 342 (7.7%) 0.38
 Acute coronary syndrome 4143 (43.0%) 2574 (49.5%) 1569 (35.4%)  < 0.001
 Heart failure 3778 (39.2%) 1617 (31.1%) 2161 (48.8%)  < 0.001
 Atrial fibrillation 3076 (31.9%) 1380 (26.5%) 1696 (38.3%)  < 0.001
 Any organ failure 3471 (36.0%) 1388 (26.7%) 2083 (47.0%)  < 0.001
 Multi-organ failure 1549 (16.1%) 607 (11.7%) 942 (21.3%)  < 0.001
 Respiratory failure 1845 (19.1%) 812 (15.6%) 1033 (23.3%)  < 0.001
 Acute kidney injury 2013 (20.9%) 666 (12.8%) 1347 (30.4%)  < 0.001
 Sepsis 649 (6.7%) 186 (3.6%) 463 (10.4%)  < 0.001
 Gastrointestinal bleeding 398 (4.1%) 104 (2.0%) 294 (6.6%)  < 0.001
 Acute blood loss anemia 452 (4.7%) 135 (2.6%) 317 (7.2%)  < 0.001
 Procedural bleeding 725 (7.5%) 341 (6.6%) 384 (8.7%)  < 0.001
Therapies and procedures
 Invasive ventilator 1581 (16.4%) 774 (14.9%) 807 (18.2%)  < 0.001
 Noninvasive ventilator 1474 (15.3%) 635 (12.2%) 839 (18.9%)  < 0.001
 Vasoactive drugs 2407 (25.0%) 1136 (21.8%) 1271 (28.7%)  < 0.001
 > 1 vasoactive drug 1148 (11.9%) 522 (10.0%) 626 (14.1%)  < 0.001
 Dialysis 479 (5.0%) 160 (3.1%) 319 (7.2%)  < 0.001
 Coronary angiogram 5092 (52.8%) 3182 (61.1%) 1910 (43.1%)  < 0.001
 PCI 3345 (34.7%) 2124 (40.8%) 1221 (27.5%)  < 0.001
 Intra-aortic balloon pump 854 (8.9%) 483 (9.3%) 371 (8.4%) 0.12

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620 Clinical Research in Cardiology (2020) 109:616–627

Table 1  (continued) Overall popula- Patients without Patients with ane- p value

tion (n = 9644) anemia (n = 5210) mia (n = 4434)

 Pulmonary artery catheter 721 (7.5%) 339 (6.5%) 382 (8.6%)  < 0.001
 Red blood cell transfusion 1170 (12.1%) 198 (3.8%) 972 (21.9%)  < 0.001
Admission laboratory values
 Admission hemoglobin (g/dL) 12.1 ± 2.1 13.7 ± 1.3 10.3 ± 1.2  < 0.001
 Admission MCV (fL) 90.7 ± 6.0 90.8 ± 5.2 90.6 ± 6.9 0.06
 Microcytosis (MCV < 80 fL) 354 (3.7%) 94 (1.8%) 258 (6.0%)  < 0.001
 Macrocytosis (MCV > 100 fL) 526 (5.6%) 207 (4.1%) 391 (7.4%)  < 0.001
 Admission RDW (%) 14.8 ± 2.2 14.0 ± 1.6 15.6 ± 2.5  < 0.001

Data represented as mean ± standard deviation for continuous variables and number (percent) for categori-
cal variables. p value is for the comparison of patients with and without anemia, using the Student’s t test
for continuous variables and Chi-squared test for categorical variables
APACHE acute physiology and chronic health evaluation, BMI body mass index, CICU cardiac intensive
care unit, ICD International Classification of Diseases, MCV mean corpuscular volume, PCI percutaneous
coronary intervention, RDW red cell distribution width, SOFA sequential organ failure assessment

Unadjusted hospital mortality
A total of 519 (5.4%) patients died in the CICU, and 845
(8.8%) patients died in the hospital. Unadjusted CICU
mortality was higher in patients with anemia (6.5% vs.
4.4%, unadjusted OR 1.52, 95% CI 1.28–1.82, p < 0.001),
as was unadjusted hospital mortality (11.3% vs. 6.6%,
unadjusted OR 1.82, 95% CI 1.58–2.10, p < 0.001). Similar
results were observed when using the WHO gender-spe-
cific definition of anemia: both CICU mortality (6.4% vs.
4.1%, unadjusted OR 1.58, 95% CI 1.31–1.90, p < 0.001)
and hospital mortality (10.8% vs. 6.2%, unadjusted OR
1.84, 95% CI 1.58–2.14, p < 0.001) were higher in patients
with anemia. There was a stepwise increase in hospital
mortality with decreasing admission Hb: ≥ 12 g/dL, 6.6%;
10.0–11.9  g/dL, 10.1%; 8.0–9.9  g/dL, 13.0%; < 8  g/dL
16.4% (p < 0.001). Admission Hb was inversely associ-
ated with hospital mortality (unadjusted OR 0.87 per 1 g/
dL, 95% CI 0.84–0.90, p < 0.001), with an optimal cutoff
of 11.5 g/dL for predicting hospital mortality. The unad-
justed OR value for admission Hb was 0.84 per 1 g/dL
(95% CI 0.78–0.90) among patients with anemia and 1.08
per 1 g/dL (95% CI 1.00–1.17) in patients without anemia,
reflecting a U-shaped relationship between admission Hb
and mortality (Fig. 1). Admission MCV was positively
associated with hospital mortality (unadjusted OR 1.04

Fig. 1  CICU and hospital mor-

tality as a function of admission
hemoglobin. p < 0.001 for both
CICU and hospital mortality
across groups using Chi-squared
test. CICU cardiac intensive
care unit

13
Clinical Research in Cardiology (2020) 109:616–627 621

per 1 fL, 95% CI 1.02–1.05 p < 0.001), with an optimal
cutoff of 94.6 fL for predicting hospital mortality. This
relationship was similar among patients with anemia (OR
1.03 per 1 fL, 95% CI 1.02–1.05) and patients without
anemia (OR 1.04 per 1 fL, 95% CI 1.01–1.06). A J-shaped
relationship was observed between admission MCV and
mortality (Fig. 2a); the MCV was associated with hospi-
tal mortality in patients with and without anemia, with
mortality being highest in patients with macrocytic ane-
mia (Fig. 2b). Admission RDW was positively associated
with hospital mortality (unadjusted OR 1.20 per 1%, 95%
CI 1.17–1.23, p < 0.001), with an optimal cutoff of 14.3%
for predicting hospital mortality. This association that
appeared to be stronger in patients without anemia (unad-
justed OR 1.34 per 1%, 95% CI 1.28–1.41) compared to
patients with anemia (unadjusted OR 1.11 per 1%, 95%
CI 1.08–1.15). A progressive increase in mortality was
observed with increasing decile of RDW, both in patients
with and without anemia (Fig. 3).

Fig. 2  a CICU and hospital

mortality as a function of
admission MCV. p < 0.001
for both CICU and hospital
mortality across groups using
Chi-squared test. CICU cardiac
intensive care unit, MCV
mean corpuscular volume. b
CICU and hospital mortality
in patients with microcytosis
(MCV < 80 fL), macrocytosis
(MCV > 100 fL) and normocy-
tosis (MCV 80–100 fL), with
and without anemia. p < 0.001
for both CICU and hospital
mortality between groups using
Chi-squared test. CICU cardiac
intensive care unit, MCV mean
corpuscular volume

13

622
Fig. 3  Hospital mortality as a
function of admission RDW
decile in the overall popula-
tion, patients with anemia,
and patients without anemia.
p < 0.001 for hospital mortality
trends across RDW declines
in each group. RDW red cell
distribution width
Adjusted hospital mortality
On multivariable regression adjusting for demographics,
comorbidities, vital signs, laboratory data, discharge diagno-
ses and APACHE-III score (Table 2), neither admission Hb
level nor anemia (both p > 0.99) was associated with hospi-
tal mortality. Likewise, admission MCV (adjusted OR 1.01
per 1 fL, 95% CI 1.00–1.03, p = 0.11) was not significantly
associated with hospital mortality. By contrast, admission
RDW remained strongly associated with hospital mortality
after multivariable adjustment (adjusted OR 1.15 per 1%,
95% CI 1.10–1.21, p < 0.001). There was a positive statisti-
cal interaction between admission Hb and RDW (p = 0.005).
Post‑discharge survival
Among 8799 (91.2%) patients surviving to hospital dis-
charge, 3537 (40.2%) died during a mean follow-up of
3.4 years; 1229 (14.0%) hospital survivors had post-dis-
charge follow-up less than 1 year, including loss to follow-
up. Post-discharge survival decreased in a stepwise fashion
as a function of decreasing quartile of admission Hb (Fig. 4a,
p < 0.001 by log-rank). Post-discharge survival differed
based on the presence or absence of anemia and the admis-
sion MCV (Fig. 4b, p < 0.001 by log-rank); survival was
highest among patients with normocytosis or microcytosis
without anemia and lowest among patients with macrocytic
anemia. Post-discharge survival decreased in a stepwise
fashion as a function of increasing quartile of admission
Hb (Fig. 4c, p < 0.001 by log-rank). On Cox proportional-
hazards analysis adjusting for predictors of hospital mortal-
ity (Table 2), admission Hb (adjusted HR 0.92 per 1 g/dL,
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Clinical Research in Cardiology (2020) 109:616–627
95% CI 0.90–0.94), MCV (adjusted HR 1.02 per 1 fL, 95%
CI 1.01–1.02), and RDW (adjusted HR per 1% 1.13, 95% CI
1.11–1.15) were all significantly (p < 0.001) associated with
post-discharge mortality among hospital survivors.
Discussion
To our knowledge, this is the largest study to examine the
associations between hematologic indices with hospital and
post-discharge mortality in unselected CICU patients. Ane-
mia (admission Hb < 12 g/dL) was present in almost 50% of
patients in this CICU population and predicted higher unad-
justed hospital and post-discharge mortality. Admission Hb
demonstrated a reverse J-shaped relationship with hospital
mortality, but this relationship did not persist after multi-
variable adjustment. Admission MCV showed a J-shaped
association with hospital mortality, and patients with mac-
rocytic anemia were at higher risk of hospital and post-dis-
charge death. An elevated admission RDW was associated
with higher hospital and post-discharge mortality, and RDW
remained a significant predictor of hospital mortality after
multivariable adjustment. The association between RDW
and mortality was influenced by the presence or absence of
anemia, as evidenced by the significant statistical interaction
term on multivariable regression. The relationship between
RDW and mortality appeared stronger in patients without
anemia, suggesting that elevated RDW was a relevant prog-
nostic factor and not merely a marker of anemia. Admission
Hb, MCV, and RDW were all significantly associated with
adjusted post-discharge mortality among hospital survivors.
Patients with HF had lower Hb and higher RDW, as opposed
Clinical Research in Cardiology (2020) 109:616–627 623

Table 2  Predictors of hospital mortality using multivariable regression using an adaptive elastic net penalty algorithm and predictors of post-
discharge mortality using Cox proportional-hazards analysis
Variable Inpatient mortality (regression) Post-discharge mortality (Cox)
Adjusted OR 95% CI p value Adjusted HR 95% CI p value

Comorbidities and severity of illness

 Age (per 1 year) 1.03 1.02–1.04  < 0.001 1.03 1.02–1.03  < 0.001
 Inpatient days prior to CICU 1.01 0.98–1.03 0.63 1.00 0.98–1.01 0.63
 Charlson Comorbidity Index 1.02 0.98–1.07 0.31 1.12 1.10–1.14  < 0.001
 Prior stroke 1.04 0.74–1.44 0.83 1.02 0.91–1.14 0.74
 APACHE-III score (per 1 unit) 1.02 1.02–1.03  < 0.001 1.01 1.00–1.01  < 0.001
Admission vital signs
 Systolic BP (per 1 mmHg) 1.00 0.99–1.00 0.13 1.00 1.00–1.00 0.02
 Heart rate (per 1 BPM) 1.01 1.00–1.01 0.02 1.00 1.00–1.00 0.01
 Respiratory rate (per 1 BPM) 1.01 0.99–1.03 0.47 1.01 1.00–1.02 0.02
Admission laboratory values
 Hemoglobin (per 1 g/dL)* –- –- –- 0.92 0.90–0.94  < 0.001
 MCV (per 1 fL) 1.01 1.00–1.03 0.11 1.02 1.01–1.02  < 0.001
 RDW (per 1%) 1.15 1.10–1.21  < 0.001 1.13 1.11–1.15  < 0.001
 Anion gap (per 1 mEq/L) 1.04 1.01–1.07 0.008 0.99 0.98–1.00 0.21
 Chloride (per 1 mEq/L) 0.96 0.94–0.98  < 0.001 0.97 0.96–0.98  < 0.001
 Neutrophil count (per 1000/mm3) 1.03 1.01–1.07 0.002 1.00 0.99–1.01 0.89
 BUN (per 1 mg/dL) 1.01 1.00–1.01 0.06 1.00 1.00–1.01  < 0.001
Procedures and therapies
 # vasoactive drugs (per 1 drug) 1.45 1.30–1.62  < 0.001 1.04 0.98–1.11 0.17
 Dialysis in CICU 2.00 1.35–2.96  < 0.001 1.58 1.33–1.88  < 0.001
 Pulmonary artery catheter 0.75 0.51–1.09 0.14 0.86 0.73–1.02 0.08
 Coronary angiogram 0.93 0.70–1.23 0.59 0.91 0.82–1.01 0.08
 PCI 0.74 0.54–1.01 0.05 0.80 0.71–0.89  < 0.001
Discharge ICD9 diagnoses
 Shock 1.32 0.94–1.85 0.11 0.96 0.82–1.13 0.66
 Hypertension 0.55 0.43–0.70  < 0.001 0.84 0.77–0.91  < 0.001
 Cardiomyopathy 0.76 0.56–1.04 0.08 1.02 0.90–1.16 0.73
 Heart failure 0.82 0.63–1.06 0.14 1.26 1.14–1.39  < 0.001
 Atrial fibrillation 0.79 0.63–1.01 0.06 1.10 1.01–1.20 0.03
 Cardiac arrest 3.56 2.59–4.89  < 0.001 1.00 0.82–1.20 0.96
 Acute coronary syndrome 1.08 0.79–1.48 0.63 1.08 0.97–1.21 0.17
 Coronary artery disease 0.69 0.53–0.90 0.007 0.94 0.85–1.04 0.22
 Acute kidney injury 1.06 0.81–1.37 0.69 1.02 0.91–1.12 0.75
 Respiratory failure 2.21 1.68–2.90  < 0.001 1.18 1.06–1.32 0.003
 Procedural bleeding 1.47 0.97–2.23 0.07 0.82 0.69–0.97 0.02

Adjusted odds ratio (OR) and 95% confidence interval (CI) values are shown
APACHE acute physiology and chronic health evaluation, BUN blood urea nitrogen, CICU cardiac intensive care unit, MCV mean corpuscular
volume, PCI percutaneous coronary intervention, RDW red cell distribution width
*
 Admission Hb was not selected for inclusion in the final regression model for hospital mortality

to patients with ACS, implying an association between myo-
cardial dysfunction and these hematologic abnormalities.
These data emphasize the importance of easily-available
hematologic laboratory data for risk stratification of CICU
patients and highlight the interactions between hematologic
abnormalities and acute cardiovascular disease outcomes.
Anemia has been associated with adverse outcomes
across a broad spectrum of patients with acute cardiovas-
cular disease and critical illness [1–5, 15]. We observed the
same curvilinear relationship between admission Hb and
unadjusted hospital mortality in our CICU population, as
was previously reported in ACS patients [4]. However, after

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624
Fig. 4  a Kaplan–Meier curves demonstrating post-hospital survival
among hospital survivors, grouped by admission hemoglobin quar-
tile, based on a median of 12.2 (IQR 10.6–13.7) g/dL. p < 0.001
between groups by log-rank. b Kaplan–Meier curves demonstrating
post-hospital survival among hospital survivors, grouped by RDW
quartile based on a mean RDW of 14.1% (IQR 13.3–15.6). p < 0.001
multivariable adjustment we did not observe an association
between admission Hb and hospital mortality in this large
CICU population, potentially suggesting that anemia may
be a marker of sicker CICU patients rather than a directly
pathological entity in many cases [15]. Our findings imply
that acutely raising the Hb level, for instance by transfu-
sion, may not necessarily reduce mortality in CICU patients,
consistent with prior studies that have failed to demonstrate
improved outcomes using higher Hb thresholds for transfu-
sion among patients with acute cardiovascular disease [28].
This highlights the importance of ongoing studies such
as the Myocardial Ischemia and Transfusion trial (MINT,
NCT02981407) to define the role of transfusion in acutely-ill
cardiac patients with anemia.
Unlike our results for hospital mortality, a lower admis-
sion Hb was associated with higher post-discharge mortal-
ity among hospital survivors. A prior study by Uscinska,
et al. found that lower Hb levels and decreased markers of
iron stores were associated with lower long-term survival in
their cohort of 392 CICU patients [7]. Anemia and iron defi-
ciency have been identified as relevant prognostic variables
13
Clinical Research in Cardiology (2020) 109:616–627
between groups by log-rank. RDW, red cell distribution width. c
Kaplan–Meier curves demonstrating post-hospital survival among
hospital survivors, grouped by admission MCV and the presence of
anemia (admission hemoglobin < 12 g/dL). p < 0.001 between groups
by log-rank. MCV mean corpuscular volume
and important targets for therapy in patients with HF [29,
30]. Chronic iron deficiency typically produces microcyto-
sis with an elevated RDW, although macrocytosis can be
seen during acute blood loss due to regenerative reticulocy-
tosis [30]. In our CICU population, macrocytosis appeared
to be more strongly associated with adverse outcomes than
microcytosis, raising important questions about the under-
lying pathophysiology that drives the associations between
anemia, MCV and outcomes.
The association between MCV and mortality has not been
previously explored in unselected CICU patients, and our
results suggest that an elevated MCV is more significantly
associated with post-discharge than hospital mortality.
Huang et al. demonstrated an association between higher
MCV and higher RDW with increased unadjusted hospital
mortality among acute MI patients in the ICU; as in our
study, Hb levels were associated with unadjusted mortal-
ity but not adjusted mortality [12]. The mean corpuscular
Hb concentration was inversely related to adjusted hos-
pital mortality in their population, and RDW was associ-
ated with adjusted 1-year mortality. Similarly, Ueda et al.
Clinical Research in Cardiology (2020) 109:616–627 625
demonstrated that an elevated MCV is associated with
mortality among patients with acute HF [6]. Prior studies
have shown associations between elevated MCV with mor-
tality and ICU readmission in other ICU populations [14,
16]. Bazick et al. previously demonstrated a higher MCV to
be associated with increased hospital mortality in a cohort
of 51,143 mixed ICU patients (including 15% with MI and
22% with HF), after performing multivariable adjustment
[16]. Numerous potential pathophysiologic mechanisms may
explain the association between elevated MCV and adverse
outcomes, including altered hematopoiesis due to intrinsic
bone marrow abnormalities, organ dysfunction, drugs, tox-
ins, and nutritional deficiency which may influence macro-
cyte morphology and produce concomitant cytopenias [23].
An elevated MCV may represent myelodysplastic syndrome
or clonal hematopoiesis of indeterminate potential (CHIP),
the latter of which has been associated with an increased risk
of cardiovascular events and highlighted as a potent emerg-
ing cardiovascular risk factor [31, 32].
RDW was one of the most significant predictors of
the adjusted hospital and post-discharge mortality in this
CICU cohort and appeared to be more strongly associ-
ated with mortality among patients without anemia, even
though patients with anemia had higher RDW. These find-
ings in a mixed CICU population may be expected given
the consistent association between an elevated RDW and
increased mortality in patients with acute cardiovascular
disease and general ICU patients [9–11, 14, 16–18]. A prior
study by Hu, et al. demonstrated an association between
elevated RDW with hospital mortality and AKI in 412
CICU patients, even after adjustment for illness severity
and other variables, higher RDW was associated with lower
long-term survival [8]. These authors found a positive cor-
relation between RDW and the APACHE-II score, suggest-
ing that RDW correlates with illness severity yet provides
additional prognostic value. Prior studies in patients with
acute myocardial infarction have consistently demonstrated
that an elevated RDW is associated with higher mortality,
even after adjustment for relevant risk scores [10]. Similar
associations between elevated RDW and death have been
reported in patients with acute HF, including patients with
and without anemia [9]. In one of the largest studies exam-
ining RDW in critically ill patients, Bazick et al. reported a
strong independent relationship between RDW and mortal-
ity [16]. As in our study, patients with elevated RDW were
older, had greater comorbidities, more frequently had sepsis,
had a worse renal function and lower Hb levels, and had a
higher prevalence of organ failure.
Several potential hypotheses have been proposed to
explain the association between elevated RDW and mor-
tality, which is undoubtedly multifactorial and likely medi-
ated by higher illness severity and worse underlying car-
diac substrate [9, 10, 16, 17]. The factors which may drive
both altered hematopoiesis and adverse outcomes include
increased inflammation or oxidative stress (as suggested by
studies showing correlations between RDW and C-reactive
protein) and the effects of multi-organ dysfunction (includ-
ing AKI) and baseline comorbidities on bone marrow func-
tion and hematopoiesis [9, 10, 15–17]. While an elevated
RDW clearly portends higher hospital and post-discharge
mortality risk independent of anemia, it remains uncertain
how to leverage this information to optimize treatment for
CICU patients.
Limitations
This study has a number of relevant limitations that apply
similarly to other retrospective cohort analyses, particularly
the potential for additional unmeasured confounding vari-
ables. The CICU population at Mayo Clinic may differ from
other populations in terms of baseline demographics and
case mix [19]. We focused on admission laboratory values
to predict mortality and were not able to determine whether
changes in these variables during hospitalization influenced
mortality risk. We did not have data available on pre-admis-
sion laboratory values, prior hematologic abnormalities,
preceding transfusion, blood cell morphology, hemolysis,
reticulocytosis, bleeding, iron studies, or vitamin levels. This
prevented us from determining the causes and chronicity of
anemia, elevated MCV, or elevated RDW in our patients,
and from defining how these hematologic abnormalities may
have led to higher mortality. Likewise, we did not have echo-
cardiographic data available to better elucidate the relation-
ships between HF and myocardial dysfunction with abnor-
mal hematologic parameters. Our post-discharge mortality
analysis should be considered exploratory, as the use of elec-
tronic health record review to determine patient death may
underestimate post-discharge mortality by potentially failing
to capture patients dying in other health systems. We did not
have data available to determine cause of death, preventing
us from providing specific insights about the mechanisms
that could have linked abnormal hematologic indices with
mortality risk.
Conclusions
Anemia is common among CICU patients and is associated
with higher unadjusted short-term and long-term mortal-
ity, but this relationship seems to be mediated primarily by
illness severity and comorbidities. By contrast, elevated
RDW was strongly associated with higher hospital mortal-
ity after adjusting for relevant covariates, as shown in other
populations of cardiac and ICU patients. Anemia, MCV,
and RDW were able to risk-stratify post-discharge mortal-
ity among hospital survivors. Incorporation of RDW into
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626
future severity of illness scores may be useful for enhanc-
ing mortality risk stratification. Future studies are needed to
understand the relationship between RDW and outcomes in
CICU patients to determine whether RDW reflects specific
underlying pathophysiology or simply greater illness sever-
ity and to better define the underlying pathophysiology link-
ing abnormal hematopoiesis and outcomes in patients with
acute cardiovascular disease.
Acknowledgements  The authors would like to acknowledge the dedi-
cated physicians, nurses and allied health staff comprising the multi-
disciplinary team that cares for our CICU patients each day.
Funding  No extramural funding was involved in the conduct of this
research.
Compliance with ethical standards  DA, White HD (2018) Fourth universal definition of myocardial
Conflict of interest  The authors report no relevant conflicts of interest.
References
1. Lawler PR, Filion KB, Dourian T, Atallah R, Garfinkle M,
Eisenberg MJ (2013) Anemia and mortality in acute coronary
syndromes: a systematic review and meta-analysis. Am Heart J
165(2):143–153 e145
2. Kajimoto K, Sato N, Takano T, Investigators of the Acute Decom-
pensated Heart Failure Syndromes r (2015) Association between
anemia, clinical features and outcome in patients hospitalized for
acute heart failure syndromes. Eur Heart J Acute Cardiovasc Care
4(6):568–576
3. Kwok CS, Tiong D, Pradhan A, Andreou AY, Nolan J, Bertrand
OF, Curzen N, Urban P, Myint PK, Zaman AG et  al (2016)
Meta-analysis of the prognostic impact of anemia in patients
undergoing percutaneous coronary intervention. Am J Cardiol
118(4):610–620
4. Brener SJ, Mehran R, Dangas GD, Ohman EM, Witzenbichler
B, Zhang Y, Parvataneni R, Stone GW (2017) Relation of base-
line hemoglobin levels and adverse events in patients with acute
coronary syndromes (from the Acute Catheterization and Urgent
Intervention Triage strategY and Harmonizing Outcomes with
RevasculariZatiON and Stents in Acute Myocardial Infarction
Trials). Am J Cardiol 119(11):1710–1716
5. Backhaus T, Fach A, Schmucker J, Fiehn E, Garstka D, Stehmeier
J, Hambrecht R, Wienbergen H (2018) Management and predic-
tors of outcome in unselected patients with cardiogenic shock
complicating acute ST-segment elevation myocardial infarc-
tion: results from the Bremen STEMI Registry. Clin Res Cardiol
107(5):371–379
6. Ueda T, Kawakami R, Horii M, Sugawara Y, Matsumoto T, Okada
S, Nishida T, Soeda T, Okayama S, Somekawa S et al (2013) High
mean corpuscular volume is a new indicator of prognosis in acute
decompensated heart failure. Circ J 77(11):2766–2771
7. Uscinska E, Sobkowicz B, Lisowska A, Sawicki R, Dabrowska
M, Szmitkowski M, Musial WJ, Tycinska AM (2016) Predictors
of long-term mortality in patients hospitalized in an Intensive
Cardiac Care Unit. Int Heart J 57(1):67–72
8. Hu Y, Liu H, Fu S, Wan J, Li X (2017) Red blood cell distri-
bution width is an independent predictor of AKI and mortality
in patients in the Coronary Care Unit. Kidney Blood Press Res
42(6):1193–1204
13
Clinical Research in Cardiology (2020) 109:616–627
9. Cheng YL, Cheng HM, Huang WM, Lu DY, Hsu PF, Guo CY,
Yu WC, Chen CH, Sung SH (2016) Red cell distribution width
and the risk of mortality in patients with acute heart failure
with or without cardiorenal anemia syndrome. Am J Cardiol
117(3):399–403
10. Abrahan LLT, Ramos JDA, Cunanan EL, Tiongson MDA, Pun-
zalan FER (2018) Red cell distribution width and mortality in
patients with acute coronary syndrome: a meta-analysis on prog-
nosis. Cardiol Res 9(3):144–152
11. Uemura Y, Shibata R, Takemoto K, Uchikawa T, Koyasu M,
Watanabe H, Mitsuda T, Miura A, Imai R, Watarai M et al (2016)
Elevation of red blood cell distribution width during hospitaliza-
tion predicts mortality in patients with acute decompensated heart
failure. J Cardiol 67(3):268–273
12. Huang YL, Hu ZD (2016) Lower mean corpuscular hemoglobin
concentration is associated with poorer outcomes in intensive
care unit admitted patients with acute myocardial infarction. Ann
Transl Med 4(10):190
13. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow
infarctio. J Am Coll Cardiol 2018:25285
14. Tonietto TA, Boniatti MM, Lisboa TC, Viana MV, Dos Santos
MC, Lincho CS, Pellegrini JAS, Vidart J, Neyeloff JL, Faulhaber
GAM (2018) Elevated red blood cell distribution width at ICU
discharge is associated with readmission to the intensive care unit.
Clin Biochem 55:15–20
15. Hayden SJ, Albert TJ, Watkins TR, Swenson ER (2012) Anemia
in critical illness: insights into etiology, consequences, and man-
agement. Am J Respir Crit Care Med 185(10):1049–1057
16. Bazick HS, Chang D, Mahadevappa K, Gibbons FK, Christopher
KB (2011) Red cell distribution width and all-cause mortality in
critically ill patients. Crit Care Med 39(8):1913–1921
17. Luo R, Hu J, Jiang L, Zhang M (2016) Prognostic value of red
blood cell distribution width in non-cardiovascular critically or
acutely patients: a systematic review. PLoS ONE 11(12):e0167000
18. Fujita B, Franz M, Figulla HR, Pfeifer R, Kabisch B, Fritzen-
wanger M, Jung C (2015) Red cell distribution width and sur-
vival in patients hospitalized on a medical ICU. Clin Biochem
48(16–17):1048–1052
19. Goldfarb M, van Diepen S, Liszkowski M, Jentzer JC, Pedraza I,
Cercek B: Noncardiovascular Disease and Critical Care Delivery
in a Contemporary Cardiac and Medical Intensive Care Unit. J
Intensive Care Med 2017:885066617741873.
20. Bennett CE, Wright RS, Jentzer J, Gajic O, Murphree DH, Mur-
phy JG, Mankad SV, Wiley BM, Bell MR, Barsness GW (2019)
Severity of illness assessment with application of the APACHE IV
predicted mortality and outcome trends analysis in an academic
cardiac intensive care unit. J Crit Care 50:242–246
21. Jentzer JC, Bennett C, Wiley BM, Murphree DM, Keegan MT,
Gajic O, Wright RS, Barsness GW (2018) Predictive value of
the sequential organ failure assessment score for mortality in a
contemporary cardiac intensive care unit population. J Am Heart
Assoc 7(6):e008169
22. Jentzer JC, Murphree DH, Wiley B, Bennett C, Goldfarb M,
Keegan MT, Murphy JG, Wright RS, Barsness GW (2018) Com-
parison of mortality risk prediction among patients %3e/=70 Ver-
sus %3c70 years of age in a Cardiac Intensive Care Unit. Am J
Cardiol 122(10):1773–1778
23. Cappellini MD, Motta I (2015) Anemia in clinical practice-def-
inition and classification: does hemoglobin change with aging?
Semin Hematol 52(4):261–269
24. Chandra S, Kashyap R, Trillo-Alvarez CA, Tsapenko M, Yilmaz
M, Hanson AC, Pickering BW, Gajic O, Herasevich V (2011)
Mapping physicians’ admission diagnoses to structured concepts
towards fully automatic calculation of acute physiology and
chronic health evaluation score. BMJ Open 1(2):e000216
Clinical Research in Cardiology (2020) 109:616–627 627
25. Harrison AM, Yadav H, Pickering BW, Cartin-Ceba R, Herasevich
V (2013) Validation of computerized automatic calculation of the
sequential organ failure assessment score. Crit Care Res Pract
2013:975672
26. Singh B, Singh A, Ahmed A, Wilson GA, Pickering BW,
Herasevich V, Gajic O, Li G (2012) Derivation and validation
of automated electronic search strategies to extract Charlson
comorbidities from electronic medical records. Mayo Clin Proc
87(9):817–824
27. Zou H, Hastie T (2005) Regularization and variable selection via
the elastic net. J Roy Stat Soc B 67:301–320
28. Hebert PC, Yetisir E, Martin C, Blajchman MA, Wells G, Mar-
shall J, Tweeddale M, Pagliarello G, Schweitzer I, Transfusion
Requirements in Critical Care Investigators for the Canadian Criti-
cal Care Trials G (2001) Is a low transfusion threshold safe in
critically ill patients with cardiovascular diseases? Crit Care Med
29(2):227–234
29. Wienbergen H, Pfister O, Hochadel M, Fach A, Backhaus T,
Bruder O, Remppis BA, Maeder MT, von Scheidt W, Pauschinger
M et al (2019) Long-term effects of iron deficiency in patients
with heart failure with or without anemia: the RAID-HF follow-up
study. Clin Res Cardiol 108(1):93–100
30. von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD
(2019) Iron deficiency in heart failure: an overview. JACC Heart
Fail 7(1):36–46
31. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz
E, McConkey M, Gupta N, Gabriel S, Ardissino D et al (2017)
Clonal hematopoiesis and risk of atherosclerotic cardiovascular
disease. N Engl J Med 377(2):111–121
32. Libby P, Sidlow R, Lin AE, Gupta D, Jones LW, Moslehi J, Zeiher
A, Jaiswal S, Schulz C, Blankstein R et al (2019) Clonal hemat-
opoiesis: crossroads of aging, cardiovascular disease, and cancer:
JACC review topic of the week. J Am Coll Cardiol 74(4):567–577
13